J.S. Bell's Concept of Local Causality

John Stewart Bell's famous 1964 theorem is widely regarded as one of the most important developments in the foundations of physics. It has even been described as "the most profound discovery of science." Yet even as we approach the 50th anniversary of Bell's discovery, its meaning and implications remain controversial. Many textbooks and commentators report that Bell's theorem refutes the possibility (suggested especially by Einstein, Podolsky, and Rosen in 1935) of supplementing ordinary quantum theory with additional ("hidden") variables that might restore determinism and/or some notion of an observer-independent reality. On this view, Bell's theorem supports the orthodox Copenhagen interpretation. Bell's own view of his theorem, however, was quite different. He instead took the theorem as establishing an "essential conflict" between the now well-tested empirical predictions of quantum theory and relativistic \emph{local causality}. The goal of the present paper is, in general, to make Bell's own views more widely known and, in particular, to explain in detail Bell's little-known mathematical formulation of the concept of relativistic local causality on which his theorem rests. We thus collect and organize many of Bell's crucial statements on these topics, which are scattered throughout his writings, into a self-contained, pedagogical discussion including elaborations of the concepts "beable", "completeness", and "causality" which figure in the formulation. We also show how local causality (as formulated by Bell) can be used to derive an empirically testable Bell-type inequality, and how it can be used to recapitulate the EPR argument.Comment: 19 pages, 4 figure

Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other microRNAs

Most metazoan microRNAs (miRNAs) target many genes for repression, but the nematode lsy-6 miRNA is much less proficient. Here we show that the low proficiency of lsy-6 can be recapitulated in HeLa cells and that miR-23, a mammalian miRNA, also has low proficiency in these cells. Reporter results and array data indicate two properties of these miRNAs that impart low proficiency: their weak predicted seed-pairing stability (SPS) and their high target-site abundance (TA). These two properties also explain differential propensities of small interfering RNAs (siRNAs) to repress unintended targets. Using these insights, we expand the TargetScan tool for quantitatively predicting miRNA regulation (and siRNA off-targeting) to model differential miRNA (and siRNA) proficiencies, thereby improving prediction performance. We propose that siRNAs designed to have both weaker SPS and higher TA will have fewer off-targets without compromised on-target activity.National Institutes of Health (U.S.) (grant GM067031)Seoul National University (Research Settlement Fund)Howard Hughes Medical Institute (Investigator

Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis

We describe a large-scale random approach termed reduced representation bisulfite sequencing (RRBS) for analyzing and comparing genomic methylation patterns. BglII restriction fragments were size-selected to 500–600 bp, equipped with adapters, treated with bisulfite, PCR amplified, cloned and sequenced. We constructed RRBS libraries from murine ES cells and from ES cells lacking DNA methyltransferases Dnmt3a and 3b and with knocked-down (kd) levels of Dnmt1 (Dnmt[1(kd),3a(−/−),3b(−/−)]). Sequencing of 960 RRBS clones from Dnmt[1(kd),3a(−/−),3b(−/−)] cells generated 343 kb of non-redundant bisulfite sequence covering 66212 cytosines in the genome. All but 38 cytosines had been converted to uracil indicating a conversion rate of >99.9%. Of the remaining cytosines 35 were found in CpG and 3 in CpT dinucleotides. Non-CpG methylation was >250-fold reduced compared with wild-type ES cells, consistent with a role for Dnmt3a and/or Dnmt3b in CpA and CpT methylation. Closer inspection revealed neither a consensus sequence around the methylated sites nor evidence for clustering of residual methylation in the genome. Our findings indicate random loss rather than specific maintenance of methylation in Dnmt[1(kd),3a(−/−),3b(−/−)] cells. Near-complete bisulfite conversion and largely unbiased representation of RRBS libraries suggest that random shotgun bisulfite sequencing can be scaled to a genome-wide approach

Predicting fear of breast cancer recurrence and self-efficacy in survivors by age at diagnosis

PURPOSE/OBJECTIVES: To determine the effect that age at diagnosis has on fear of breast cancer recurrence and to identify the predictors of fear of recurrence using self-efficacy as a mediator. DESIGN: Cross-sectional survey. SETTING: Two university cancer centers and one cooperative group in the midwestern United States. SAMPLE: 1,128 long-term survivors. METHODS: Survivors were eligible if they were aged 18-45 years (younger group) or 55-70 years (older group) at cancer diagnosis, had received chemotherapy, and were three to eight years postdiagnosis. Fear of recurrence was compared between younger and older groups. Multiple regression analyses were used to test variables' prediction of fear of recurrence and breast cancer survivor self-efficacy, as well as breast cancer survivor self-efficacy mediation effects. MAIN RESEARCH VARIABLES: Fear of recurrence, breast cancer survivor self-efficacy, and age at diagnosis. FINDINGS: Survivors diagnosed at a younger age had significantly higher fear of recurrence, as well as health, role, womanhood, death, and parenting worries. Perceived risk of recurrence, trait anxiety, and breast cancer reminders explained significant variance in fear of recurrence and breast cancer survivor self-efficacy. Breast cancer survivor self-efficacy partially mediated the effects of variables on fear of recurrence. CONCLUSIONS: The findings suggest that breast cancer survivor self-efficacy may have a protective effect for survivors who are younger at diagnosis and have higher perceived risk of recurrence, higher trait anxiety, and more breast cancer reminders. Oncology nurses already use the skills required to support self-efficacy. Additional research is needed to define and test breast cancer survivor self-efficacy interventions. IMPLICATIONS FOR NURSING: Oncology nurses are in a key role to assess fear of recurrence and provide self-efficacy interventions to reduce it in breast cancer survivors. Strategies to efficiently address fear of recurrence to reduce psychological distress in survivorship follow-up care are warranted

A relativistically covariant version of Bohm's quantum field theory for the scalar field

We give a relativistically covariant, wave-functional formulation of Bohm's quantum field theory for the scalar field based on a general foliation of space-time by space-like hypersurfaces. The wave functional, which guides the evolution of the field, is space-time-foliation independent but the field itself is not. Hence, in order to have a theory in which the field may be considered a beable, some extra rule must be given to determine the foliation. We suggest one such rule based on the eigen vectors of the energy-momentum tensor of the field itself.Comment: 1 figure. Submitted to J Phys A. 20/05/04 replacement has additional references and a few minor changes made for clarity. Accepted by J Phys

MERAV: a tool for comparing gene expression across human tissues and cell types

The oncogenic transformation of normal cells into malignant, rapidly proliferating cells requires major alterations in cell physiology. For example, the transformed cells remodel their metabolic processes to supply the additional demand for cellular building blocks. We have recently demonstrated essential metabolic processes in tumor progression through the development of a methodological analysis of gene expression. Here, we present the Metabolic gEne RApid Visualizer (MERAV, http://merav.wi.mit.edu), a web-based tool that can query a database comprising ∼4300 microarrays, representing human gene expression in normal tissues, cancer cell lines and primary tumors. MERAV has been designed as a powerful tool for whole genome analysis which offers multiple advantages: one can search many genes in parallel; compare gene expression among different tissue types as well as between normal and cancer cells; download raw data; and generate heatmaps; and finally, use its internal statistical tool. Most importantly, MERAV has been designed as a unique tool for analyzing metabolic processes as it includes matrixes specifically focused on metabolic genes and is linked to the Kyoto Encyclopedia of Genes and Genomes pathway search.United States. National Institutes of Health (CA103866)United States. National Institutes of Health (AI47389)Life Sciences Research FoundationMassachusetts Institute of Technology. Ludwig Center for Molecular OncologyHoward Hughes Medical Institut

Synthesis of 2-BMIDA indoles via heteroannulation : applications in drug scaffold and natural product synthesis

G.E.B. thanks the EPSRC and GSK for a PhD studentship. J.W.B.F. thanks the Leverhulme Trust for postdoctoral funding (RPG-2018-362).A Pd-catalyzed heteroannulation approach for the synthesis of C2 borylated indoles is reported. The process allows access to highly functionalized 2-borylated indole scaffolds with complete control of regioselectivity. The utility of the process is demonstrated in the synthesis of borylated sulfa drugs and in the concise synthesis of the Aspidosperma alkaloid Goniomitine.Publisher PDFPeer reviewe

Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model

MicroRNAs (miRNAs) are increasingly implicated in the regulation of metastasis. Despite their potential as targets for anti-metastatic therapy, miRNAs have only been silenced in normal tissues of rodents and nonhuman primates. Therefore, the development of effective approaches for sequence-specific inhibition of miRNAs in tumors remains a scientific and clinical challenge. Here we show that systemic treatment of tumor-bearing mice with miR-10b antagomirsa class of chemically modified anti-miRNA oligonucleotidesuppresses breast cancer metastasis. Both in vitro and in vivo, silencing of miR-10b with antagomirs significantly decreases miR-10b levels and increases the levels of a functionally important miR-10b target, Hoxd10. Administration of miR-10b antagomirs to mice bearing highly metastatic cells does not reduce primary mammary tumor growth but markedly suppresses formation of lung metastases in a sequence-specific manner. The miR-10b antagomir, which is well tolerated by normal animals, appears to be a promising candidate for the development of new anti-metastasis agents

Extensive alternative polyadenylation during zebrafish development

The post-transcriptional fate of messenger RNAs (mRNAs) is largely dictated by their 3′ untranslated regions (3′ UTRs), which are defined by cleavage and polyadenylation (CPA) of pre-mRNAs. We used poly(A)-position profiling by sequencing (3P-seq) to map poly(A) sites at eight developmental stages and tissues in the zebrafish. Analysis of over 60 million 3P-seq reads substantially increased and improved existing 3′ UTR annotations, resulting in confidently identified 3′ UTRs for >79% of the annotated protein-coding genes in zebrafish. mRNAs from most zebrafish genes undergo alternative CPA, with those from more than a thousand genes using different dominant 3′ UTRs at different stages. These included one of the poly(A) polymerase genes, for which alternative CPA reinforces its repression in the ovary. 3′ UTRs tend to be shortest in the ovaries and longest in the brain. Isoforms with some of the shortest 3′ UTRs are highly expressed in the ovary, yet absent in the maternally contributed RNAs of the embryo, perhaps because their 3′ UTRs are too short to accommodate a uridine-rich motif required for stability of the maternal mRNA. At 2 h post-fertilization, thousands of unique poly(A) sites appear at locations lacking a typical polyadenylation signal, which suggests a wave of widespread cytoplasmic polyadenylation of mRNA degradation intermediates. Our insights into the identities, formation, and evolution of zebrafish 3′ UTRs provide a resource for studying gene regulation during vertebrate development.National Institutes of Health (U.S.) (Grant GM067031)